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Literature summary for 6.1.1.10 extracted from

  • Critchley, I.A.; Green, L.S.; Young, C.L.; Bullard, J.M.; Evans, R.J.; Price, M.; Jarvis, T.C.; Guiles, J.W.; Janjic, N.; Ochsner, U.A.
    Spectrum of activity and mode of action of REP3123, a new antibiotic to treat Clostridium difficile infections (2009), J. Antimicrob. Chemother., 63, 954-963.
    View publication on PubMed

Application

Application Comment Organism
medicine REP3123 represents a promising narrow spectrum, new mode-of-action agent with an excellent microbiological profile that warrants its further evaluation as a novel drug Staphylococcus aureus
medicine REP3123 represents a promising narrow spectrum, new mode-of-action agent with an excellent microbiological profile that warrants its further evaluation as a novel drug Haemophilus influenzae
medicine REP3123 represents a promising narrow spectrum, new mode-of-action agent with an excellent microbiological profile that warrants its further evaluation as a novel drug Escherichia coli
medicine REP3123 represents a promising narrow spectrum, new mode-of-action agent with an excellent microbiological profile that warrants its further evaluation as a novel drug Homo sapiens
medicine REP3123 represents a promising narrow spectrum, new mode-of-action agent with an excellent microbiological profile that warrants its further evaluation as a novel drug Streptococcus pneumoniae
medicine REP3123 represents a promising narrow spectrum, new mode-of-action agent with an excellent microbiological profile that warrants its further evaluation as a novel drug to combat Clostridium difficile infections Clostridioides difficile

Cloned(Commentary)

Cloned (Comment) Organism
full-length MetRS with an N-terminal His-tag is overexpressed in Escherichia coli Clostridioides difficile

Protein Variants

Protein Variants Comment Organism
D229E spontaneous resistant mutant, first step Clostridioides difficile
D229N serial passage mutant Clostridioides difficile
D229N spontaneous resistant mutant, first step Clostridioides difficile
G213C spontaneous resistant mutant, first step Clostridioides difficile
G213D spontaneous resistant mutant, first step Clostridioides difficile
G54A spontaneous resistant mutant, first step Clostridioides difficile
G54C spontaneous resistant mutant, first step Clostridioides difficile
G54S spontaneous resistant mutant, first step Clostridioides difficile
G54S/L203S spontaneous resistant mutant, second step Clostridioides difficile
H101D spontaneous resistant mutant, first step Clostridioides difficile
H101L spontaneous resistant mutant, first step Clostridioides difficile
H101N spontaneous resistant mutant, first step Clostridioides difficile
H101N/G213C spontaneous resistant mutant, second step Clostridioides difficile
I105M/G213D spontaneous resistant mutant, second step Clostridioides difficile
I57N spontaneous resistant mutant, first step Clostridioides difficile
I57N/H101N spontaneous resistant mutant, second step Clostridioides difficile
T236K spontaneous resistant mutant, first step Clostridioides difficile
V216A spontaneous resistant mutant, first step Clostridioides difficile
V216F/L203S spontaneous resistant mutant, second step Clostridioides difficile

Inhibitors

Inhibitors Comment Organism Structure
REP3123 active against a collection of 108 clinical isolates of Clostridium difficile and against epidemic, moxifloxacin-resistant BI/NAP1/027 strains Clostridioides difficile
REP3123
-
Escherichia coli
REP3123
-
Haemophilus influenzae
REP3123
-
Homo sapiens
REP3123
-
Staphylococcus aureus
REP3123
-
Streptococcus pneumoniae

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
0.00055
-
tRNAMet wild-type, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.00064
-
tRNAMet mutant G54S/L203S, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.00065
-
tRNAMet mutant D229E, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.0008
-
tRNAMet mutant V216A, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.00096
-
tRNAMet mutant V216F/L203S, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.00102
-
tRNAMet mutant G54S, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.00121
-
tRNAMet mutant I57N/H101N, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.0026
-
tRNAMet mutant I57N, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.006
-
L-methionine mutant I57N, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.017
-
L-methionine mutant V216A, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.025
-
L-methionine mutant V216F/L203S, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.025
-
L-methionine wild-type, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.055
-
L-methionine mutant G54S/L203S, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.092
-
L-methionine mutant D229E, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.16
-
L-methionine mutant G54S, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.19
-
L-methionine mutant I57N/H101N, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.375
-
ATP wild-type, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.44
-
ATP mutant G54S, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.475
-
ATP mutant H101N/G213C, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.7
-
ATP mutant H101D, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.78
-
ATP mutant V216A, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.85
-
ATP mutant V216F/L203S, first step of reaction, methionyl-adenylate formation Clostridioides difficile
0.98
-
ATP mutant D229E, first step of reaction, methionyl-adenylate formation Clostridioides difficile
1
-
ATP mutant I57N, first step of reaction, methionyl-adenylate formation Clostridioides difficile
1.35
-
ATP mutant G54S/L203S, first step of reaction, methionyl-adenylate formation Clostridioides difficile
1.55
-
L-methionine mutant H101N/G213C, first step of reaction, methionyl-adenylate formation Clostridioides difficile
1.75
-
ATP mutant I57N/H101N, first step of reaction, methionyl-adenylate formation Clostridioides difficile
14.8
-
L-methionine mutant H101D, first step of reaction, methionyl-adenylate formation Clostridioides difficile

Localization

Localization Comment Organism GeneOntology No. Textmining
cytoplasm
-
Homo sapiens 5737
-
mitochondrion
-
Homo sapiens 5739
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + L-methionine + tRNAMet Staphylococcus aureus
-
AMP + diphosphate + L-methionyl-tRNAMet
-
?
ATP + L-methionine + tRNAMet Haemophilus influenzae
-
AMP + diphosphate + L-methionyl-tRNAMet
-
?
ATP + L-methionine + tRNAMet Escherichia coli
-
AMP + diphosphate + L-methionyl-tRNAMet
-
?
ATP + L-methionine + tRNAMet Homo sapiens
-
AMP + diphosphate + L-methionyl-tRNAMet
-
?
ATP + L-methionine + tRNAMet Streptococcus pneumoniae
-
AMP + diphosphate + L-methionyl-tRNAMet
-
?
ATP + L-methionine + tRNAMet Clostridioides difficile
-
AMP + diphosphate + L-methionyl-tRNAMet
-
?

Organism

Organism UniProt Comment Textmining
Clostridioides difficile
-
-
-
Escherichia coli
-
-
-
Haemophilus influenzae
-
-
-
Homo sapiens
-
-
-
Staphylococcus aureus
-
-
-
Streptococcus pneumoniae
-
-
-

Purification (Commentary)

Purification (Comment) Organism
using Ni-affinity and SourceQ anion exchange chromatography Clostridioides difficile

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + L-methionine + tRNAMet
-
Staphylococcus aureus AMP + diphosphate + L-methionyl-tRNAMet
-
?
ATP + L-methionine + tRNAMet
-
Haemophilus influenzae AMP + diphosphate + L-methionyl-tRNAMet
-
?
ATP + L-methionine + tRNAMet
-
Escherichia coli AMP + diphosphate + L-methionyl-tRNAMet
-
?
ATP + L-methionine + tRNAMet
-
Homo sapiens AMP + diphosphate + L-methionyl-tRNAMet
-
?
ATP + L-methionine + tRNAMet
-
Streptococcus pneumoniae AMP + diphosphate + L-methionyl-tRNAMet
-
?
ATP + L-methionine + tRNAMet
-
Clostridioides difficile AMP + diphosphate + L-methionyl-tRNAMet
-
?

Synonyms

Synonyms Comment Organism
methionyl-tRNA synthetase
-
Staphylococcus aureus
methionyl-tRNA synthetase
-
Haemophilus influenzae
methionyl-tRNA synthetase
-
Escherichia coli
methionyl-tRNA synthetase
-
Homo sapiens
methionyl-tRNA synthetase
-
Streptococcus pneumoniae
methionyl-tRNA synthetase
-
Clostridioides difficile
MetRS
-
Staphylococcus aureus
MetRS
-
Haemophilus influenzae
MetRS
-
Escherichia coli
MetRS
-
Homo sapiens
MetRS
-
Streptococcus pneumoniae
MetRS
-
Clostridioides difficile
MetRS1
-
Streptococcus pneumoniae
MetRS2
-
Streptococcus pneumoniae

Turnover Number [1/s]

Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
0.006
-
tRNAMet mutant V216F/L203S, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.01
-
tRNAMet mutant G54S, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.011
-
tRNAMet mutant G54S/L203S, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.013
-
tRNAMet mutant I57N/H101N, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.017
-
tRNAMet mutant I57N, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.023
-
tRNAMet mutant D229E, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.055
-
tRNAMet mutant V216A, second step of reaction, tRNA aminoacylation Clostridioides difficile
0.08
-
tRNAMet wild-type, second step of reaction, tRNA aminoacylation Clostridioides difficile
4
-
L-methionine mutant G54S, first step of reaction, methionyl-adenylate formation Clostridioides difficile
6
-
L-methionine mutant I57N/H101N, first step of reaction, methionyl-adenylate formation Clostridioides difficile
8
-
L-methionine mutant H101N/G213C, first step of reaction, methionyl-adenylate formation Clostridioides difficile
15
-
L-methionine mutant G54S/L203S, first step of reaction, methionyl-adenylate formation Clostridioides difficile
15
-
L-methionine mutant H101D, first step of reaction, methionyl-adenylate formation Clostridioides difficile
15
-
L-methionine mutant I57N, first step of reaction, methionyl-adenylate formation Clostridioides difficile
23
-
L-methionine wild-type, first step of reaction, methionyl-adenylate formation Clostridioides difficile
25
-
L-methionine mutant V216A, first step of reaction, methionyl-adenylate formation Clostridioides difficile
25
-
L-methionine mutant V216F/L203S, first step of reaction, methionyl-adenylate formation Clostridioides difficile
33
-
L-methionine mutant D229E, first step of reaction, methionyl-adenylate formation Clostridioides difficile

Cofactor

Cofactor Comment Organism Structure
ATP
-
Staphylococcus aureus
ATP
-
Haemophilus influenzae
ATP
-
Escherichia coli
ATP
-
Homo sapiens
ATP
-
Streptococcus pneumoniae
ATP
-
Clostridioides difficile

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.000000017
-
REP3123
-
Staphylococcus aureus
0.00000002
-
REP3123 wild-type Clostridioides difficile
0.00000008
-
REP3123 MetRS1 Streptococcus pneumoniae
0.0000002
-
REP3123 mutant I57N Clostridioides difficile
0.00001
-
REP3123 mutant V216F/L203S Clostridioides difficile
0.000013
-
REP3123 mutant G54S Clostridioides difficile
0.000018
-
REP3123 mutant D229E Clostridioides difficile
0.000028
-
REP3123 mitochondrial MetRS Homo sapiens
0.00007
-
REP3123 mutant V216A Clostridioides difficile
0.000155
-
REP3123 mutant I57N/H101N Clostridioides difficile
0.000178
-
REP3123
-
Haemophilus influenzae
0.000375
-
REP3123 mutant H101D Clostridioides difficile
0.0005
-
REP3123 mutant G54S/L203S Clostridioides difficile
0.001
-
REP3123 mutant H101N/G213C Clostridioides difficile
0.0019
-
REP3123
-
Escherichia coli
0.02
-
REP3123 cytoplasmic MetRS Homo sapiens
0.02
-
REP3123 MetRS2 Streptococcus pneumoniae